Mai Shibata1, Toshifumi Hatta2, Masako Saito2, Junko Toyoshima2, Yuichiro Kaneko2, Kazuo Oda3, Tetsuya Nishimura2. 1. Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-Ku, Tokyo, 103-8411, Japan. mai.shibata@astellas.com. 2. Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-Ku, Tokyo, 103-8411, Japan. 3. Astellas Research Institute of America LLC, 1 Astellas Way, Northbrook, IL, 60062, USA.
Abstract
BACKGROUND AND OBJECTIVE:Peficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects. METHODS: In this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received asingle oral dose of peficitinib (20, 60, or 200 mg) or placebo. Another cohort of Japanese men (n = 24) receivedpeficitinib (10, 30, or 100 mg) or placebo twice daily for 7 days. Pharmacokinetic and pharmacodynamic parameters were assessed, and adverse events (AEs) monitored throughout. RESULTS: Dose proportionality of maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUCinf) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized Cmax was 45.7-98.8% higher and AUCinf was 33.8-66.4% higher in Japanese versus Caucasian subjects. Meanpeak inhibition of STAT5 phosphorylation was higher in Japanese than Caucasian subjects for a given peficitinib dose, but inhibition was comparable across ethnicities for a given plasma peficitinib concentration. In the multiple-dose study, plasma peficitinib concentrations were similar on day 1 and day 7. All AEs were mild, and none resulted in study discontinuation. CONCLUSIONS:Peficitinib was well tolerated at doses up to 200 mg daily for 7 days in healthy Japanese subjects. Dose-proportional exposure was demonstrated across the single-dose range of 20-200 mg, with greater peficitinib exposure in Japanese compared with Caucasian subjects. The pharmacokinetic/pharmacodynamic relationships were considered comparable between these populations. CLINICALTRIALS. GOV IDENTIFIER: NCT01225224.
RCT Entities:
BACKGROUND AND OBJECTIVE:Peficitinib pharmacokinetics and pharmacodynamics have been characterized mainly in Caucasian subjects. This study investigated the pharmacokinetics, pharmacodynamics, safety, and tolerability of peficitinib in healthy Japanese subjects compared with Caucasian subjects. METHODS: In this single-center, randomized, double-blind, placebo-controlled study, a cohort of healthy Japanese (n = 24) and Caucasian (n = 24) men received a single oral dose of peficitinib (20, 60, or 200 mg) or placebo. Another cohort of Japanese men (n = 24) received peficitinib (10, 30, or 100 mg) or placebo twice daily for 7 days. Pharmacokinetic and pharmacodynamic parameters were assessed, and adverse events (AEs) monitored throughout. RESULTS: Dose proportionality of maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity (AUCinf) was demonstrated for both ethnicities. The geometric mean ratio for dose-normalized Cmax was 45.7-98.8% higher and AUCinf was 33.8-66.4% higher in Japanese versus Caucasian subjects. Mean peak inhibition of STAT5 phosphorylation was higher in Japanese than Caucasian subjects for a given peficitinib dose, but inhibition was comparable across ethnicities for a given plasma peficitinib concentration. In the multiple-dose study, plasma peficitinib concentrations were similar on day 1 and day 7. All AEs were mild, and none resulted in study discontinuation. CONCLUSIONS:Peficitinib was well tolerated at doses up to 200 mg daily for 7 days in healthy Japanese subjects. Dose-proportional exposure was demonstrated across the single-dose range of 20-200 mg, with greater peficitinib exposure in Japanese compared with Caucasian subjects. The pharmacokinetic/pharmacodynamic relationships were considered comparable between these populations. CLINICALTRIALS. GOV IDENTIFIER: NCT01225224.